Muscarinic agonists and antagonists

Details Muscarinic agonists and antagonists Muscarinic agonists and antagonists

2001-10-05

2002-07-23

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C546S072000, C546S097000, C544S179000, C544S182000, C544S185000, C544S194000, C544S212000, C544S216000, C544S219000, C544S238000, C544S316000, C544S319000, C544S326000, C544S330000, C544S336000, C544S406000, C544S408000, C544S409000, C514S214020, C514S252010, C514S255010, C514S256000, C514S269000, C514S252050

Reexamination Certificate

active

06423842

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to cholinergic receptor agonists and antagonists and their use as antinociception (pain relief) agents and as agents for the treatment of a variety of neurologic and psychiatric disorders. In particular, the invention relates to novel classes of azaadamantanes and azanoradamantanes.
2. Summary of the Related Art
The compounds of the invention have uses as cholinergic agonists and antagonists. As such they will have utility in modifying states where there is an imbalance in cholinergic function. An example of cholinergic deficiency is in Alzheimer's disease where there is degeneration of cholinergic neurons within the CNS. The postsynaptic muscarinic receptors in the forebrain and hippocampus persist and, therefore, muscarinic agonists have utility in treating AD by halting its progression and improving cognitive function. Cholinergic agonists also have utility in the treatment of other CNS disorders including schizophrenia or schizophreniform conditions, mania, bipolar disorders, depression and anxiety. Cholinergic agonists are particularly useful as analgesic agents and, therefore, have utility in the treatment of severe and chronic pain. Cholinergic agonists also have utility in alleviation of intraocular pressure such as found in glaucoma.
Many peripheral disease states have a basis in exaggerated cholinergic drive. Cholinergic antagonists therefore have utility in these conditions. Examples where muscarinic antagonists have utility are in bladder dysfunction, gastrointestinal motility disorders and obstructive airway disease such as COPD and asthma.
In particular, there has been considerable effort in the scientific/medical community to develop non-opiate painkillers which maintain the efficacy of opiates against severe and chronic pain but are devoid of the opiate liabilities of respiratory depression, constipation and dependence. The studies undertaken by various authors and researchers have demonstrated the importance of highly selective muscarinic agonists for use in antinociception (the treatment of pain) without the attendant undesirable side effects. The advantage of having a selective muscarinic agonist for blocking pain has been described in numerous publications. See for example, Sauerburg et al,
Life Sci.
56, 807-814 (1995); Naguib et al.,
Anesth. Analg.
85, 847-85 (1997); Eglen & Watson,
Pharmacol. Toxicol.
78, 59-68 (1996).
Jeppesen et al. WO 97/36906, entitled “Heterocyclic Compounds and their Preparation and Use,” discloses compounds comprising an unsubstituted azatricyclic heptane attached directly to a substituted or unsubstituted aromatic heterocyclic group which is a 1,2,5-thiadiazole. The compounds are claimed to be useful in treating central nervous system (“CNS”) diseases caused by malfunctioning of the muscarinic cholinergic system.
Macleod et al. WO 92/11261, entitled “4-Azatricyclo[2.2.1.0
2,6
]heptanes and Pharmaceutical Compositions,” discloses compounds comprising an unsubstituted azatricyclic heptane attached directly to a substituted or unsubstituted 5-membered aromatic heterocyclic group comprising two or three heteroatoms, at least one of which is nitrogen and another of which is oxygen or sulfur. Preferred aromatic heterocyclic groups include a 1,2,4-thiadiazole and a 1,3,4-thiadiazole. The compounds are claimed to be useful in treating neurological and mental illnesses whose clinical manifestations are due to cholinergic deficiency.
Sauerberg et al. U.S. Pat. No. 5,578,602, entitled “Certain 1-Azabicyclo[3.3.1]nonene Derivatives and Their Pharmacological Uses,” discloses compounds comprising a substituted or unsubstituted azabicyclic ring comprising from between four to ten total atoms attached directly to a substituted or unsubstituted 5-membered aromatic heterocyclic group which is a 1,2,5-thiadiazole or a 1,2,5-oxadiazole. Preferred embodiments illustrate azabicyclic rings comprising 1-azabicyclo[3.3.1]nonene, 1-azabicyclo[3.2.3]octane, 1-azabicyclo[2.2.2]octane, or 1-aza-bicyclo[2.2.1]heptane. The compounds are claimed to be useful as muscarinic agonists.
Sauerberg et al. U.S. Pat. No. 5,641,791, entitled “Heterocyclic Compounds and Their Preparation and Use,” discloses compounds comprising a substituted or unsubstituted azabicyclic octane attached directly to a substituted or unsubstituted 5-membered aromatic heterocyclic group which is a 1,2,5-thiadiazole or a 1,2,5-oxadiazole. The azabicyclic ring is 1-azabicyclo[2.2.2]octane. The compounds are claimed to be useful as muscarinic agonists.
Georgiev et al. U.S. Pat. No. 4,739,074, entitled “Adamantane Spiro-Pyrrolidene Derivatives,” discloses compounds comprising an unsubstituted tricyclic decane attached directly to a substituted or unsubstituted 5-membered non-aromatic heterocyclic group comprising one heteroatom which is nitrogen. The compounds are claimed to exhibit anti-Parkinson's activity.
Olesen et al., entitled, “3-(3-alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles. Structure-activity relationships for antinociception mediated by central muscarinic receptors,” discloses, as the title indicates, compounds of the structure:
wherein n is 1 (azanorbornanylthiadizoles) or 2 (quinuclidinylthiadiazoles) and R is alkyl, that show high affinity for muscarinic receptors and induce antinociception in vivo.
Shannon et al., entitled “In Vivo Pharmacology of Butylthio[2.2.2] (LY297802/NNCC11-1053), An Orally Acting Antinociceptive Muscarinic Agonist” discloses (+)-3(S)-3-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo[2.2.2]octane. This compound was selected for further study based on the results presented in the Olesen et al., supra. Shannon et al. suggests that this azabicyclo compound may be a selective M4 receptor agonist.
Despite the work done to date in the field there remains a need for antinociceptive agents.
SUMMARY OF THE INVENTION
The present invention brings a solution in the form of novel products that are useful as cholinergic receptor agonists and antagonists. In a preferred embodiment, the compounds of the invention can act selectively on certain muscarinic receptors, particularly on M4 receptors, with reduced cholinergic side effects. Consequently, they are well-suited for therapeutic use in the treatment of pain and other neurologic and psychiatric disorders. The compounds of the invention are members of novel classes of azaadamantanes, azanoradamantanes and azahomoadamantanes.
In addition, the invention provides pharmaceutical compositions comprising the compounds of the invention and methods of treating pain and neurologic and psychiatric disorders with the pharmaceutical compositions.
All patent applications, patents, and other publications recited herein are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The Compounds
The novel compounds of the invention are azacyclic ring systems having the formula I
including geometrical isomers, enantiomers, diastereomers, racemates, acid addition salts, salts thereof with a pharmaceutically acceptable acid, and prodrugs thereof, wherein
Q is
X is CH
2
, NH, O or S;
V, W, Y and Z independently are CH or N;
n and m independently are 0, 1, 2, 3 or 4;
R
1
and R
2
are at any position on the azacyclic ring, including the point of attachment of the heterocycle Q, and independently are hydrogen, —OH, halogen, —NH
2
, carboxy, straight or branched C
1-10
-alkyl, C
1-10
-alkenyl, or C
1-10
-alkynyl, straight or branched C
1-10
-alkoxy, or straight or branched C
1-10
-alkyl substituted with —OH, —CN, —CHO, —OH, —OR
3
, —SR
3
, —NH
2
, —NHR
3
, —NR
3
R
4
, —NO
2
, —SOR
3
, —SO
2
R
3
, —COR
3
, —CO
2
R
3
, —CONH
2
, —CONHR
3
, —CONR
3
R
4
, —CH═NOR
3
; or
R
1
and R
2
independently are phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl, each of which is unsubstituted or substituted with halogen, —CN, C
1-10
-alkyl, C
1-10
-alkoxy, or C
1-10
-alkylthio;
R is hydrogen, halogen, —CN, —C

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